Randomized comparison between KTd and KRd induction therapy followed by maintenance therapy with K or observation in transplant-ineligible patients with newly diagnosed multiple myeloma.

Randomized comparison between KTd and KRd induction followed by second randomization to carfilzomib in transplant-ineligable patients with newly diagnosed multiple myeloma.

Healthcare Resource Utilization and Cost-of-Illness in Systemic Light Chain (AL) Amyloidosis in Europe: Results From the Real-World, Retrospective EMN23 Study.

OBJECTIVES: To report healthcare resource utilization (HCRU) and safety outcomes in systemic light chain (AL) amyloidosis from the EMN23 study. MATERIALS AND METHODS: The retrospective, observational, multinational EMN23 study included 4,480 patients initiating first-line treatment for AL amyloidosis in 2004-2018 and assessed, among other objectives, HCRU and safety outcomes. HCRU included hospitalizations, examinations, and dialysis; safety included serious adverse events (SAEs) and adverse events of special interest (AESIs). Data were descriptively analyzed by select prognostic factors (e.g., cardiac staging by Mayo2004/European) for 2004-2010 and 2011-2018. A cost-of-illness analysis was conducted for the UK and Spain. RESULTS: HCRU/safety and dialysis data were extracted for 674 and 774 patients, respectively. Of patients with assessed cardiac stage (2004-2010: 159; 2011-2018: 387), 67.9% and 61.0% had ≥ 1 hospitalization, 56.0% and 51.4% had ≥ 1 SAE, and 31.4% and 28.9% had ≥ 1 AESI across all cardiac stages in 2004-2010 and 2011-2018, respectively. The per-patient-per-year length of hospitalization increased with disease severity (cardiac stage). Of patients with dialysis data (2004-2010: 176; 2011-2018: 453), 23.9% and 14.8% had ≥ 1 dialysis session across all cardiac stages in 2004-2010 and 2011-2018, respectively. The annual cost-of-illness was estimated at €40,961,066 and €31,904,386 for the UK and Spain, respectively; dialysis accounted for ∼28% (UK) and ∼35% (Spain) of the total AL amyloidosis costs. CONCLUSIONS: EMN23 showed that the burden of AL amyloidosis is substantial, highlighting the need for early disease diagnosis and effective treatments targeting the underlying pathology.

Renal outcome in multiple myeloma patients with cast nephropathy: a retrospective analysis of potential predictive values on clinical and renal outcome.

OBJECTIVE: Cast nephropathy (CN) is the leading cause of acute kidney injury (AKI) in multiple myeloma (MM). Since it is sparsely documented why some patients with CN do achieve a renal response while others do not, we describe a single-center cohort of patients with multiple myeloma and biopsy-confirmed CN to evaluate potential markers of renal response. METHODS: The data was collected as a retrospective, single-center analysis of CN-patients treated at the Medical University Vienna between 01/01/2004 and 01/01/2022. Baseline parameters and clinical outcome was compared between renal responders and non-responders. RESULTS: Among 28 patients with CN, n = 23 were assessed for renal response (14 responders; 9 non-responders). Renal responders were younger (median age: 61 years; 77 years, p = 0.039), showed higher overall survival (153months; 58months, p = 0.044) and achieved hematologic response (≥PR) to first-line therapy (p = 0.029), and complete hematologic response (CR) at any time (p = 0.025) significantly more often. Further, we could show that rapid initiation of anti-myeloma therapy after initial presentation correlated significantly with renal response (median 9 days; 27 days, p = 0.016). Analyses of kidney biopsy specimens revealed that patients with a high IF/TA score showed end stage renal disease (dialysis ≥ 3 months) significantly more often (p = <0.001). DISCUSSION: In summary, our data suggests, that a rapid start with systemic hematologic treatment in patients with MM and CN is crucial and achieving an early hematologic response is important for renal recovery. Moreover, achieving a deep hematologic response and subsequent renal recovery improves clinical outcome as reflected by an overall survival benefit.

Daratumumab in first-line treatment of patients with light chain amyloidosis and Mayo stage IIIb improves treatment response and overall survival.

Treatment of patients with Mayo stage IIIb light chain (AL) amyloidosis is still challenging, and the prognosis remains very poor. Mayo stage IIIb patients were excluded from the pivotal trial leading to the approval of daratumumab in combination with bortezomib-cyclophosphamide-dexamethasone. This retrospective, multicenter study evaluates the addition of daratumumab to first-line therapy in patients with newly diagnosed stage IIIb AL amyloidosis. In total, data from 119 consecutive patients were analyzed, 27 patients received an upfront treatment including daratumumab, 63 a bortezomibbased regimen without daratumumab, eight received therapies other than daratumumab or bortezomib and 21 pretreated patients or deceased prior to treatment were excluded. In the daratumumab group, median overall survival was not reached after a median follow-up time of 14.5 months, while it was significantly worse in the bortezomib- and the otherwise treated group (6.6 and 2.2 months, respectively) (P=0.002). Overall hematologic response rate at 2 and 6 months was better in the daratumumab group compared to the bortezomib group (59% vs. 37%, P=0.12, 67% vs. 41%, P=0.04, respectively). Landmark survival analyses revealed a significantly improved overall survival in patients with partial hematologic response or better, compared to non-responders. Cardiac response at 6 months was 46%, 21%, 0% in the daratumumab-, bortezomib- and otherwise treated groups, respectively (P=0.04). A landmark survival analysis revealed markedly improved overall survival in patients with cardiac very good partial response vs. cardiac non-responders (P=0.002). This study demonstrates for the first time the superiority of an upfront treatment with daratumumab over standard-of-care in stage IIIb AL amyloidosis.

Myocardial structural and functional changes in cardiac amyloidosis: insights from a prospective observational patient registry.

AIMS: The pathophysiological hallmark of cardiac amyloidosis (CA) is the deposition of amyloid within the myocardium. Consequently, extracellular volume (ECV) of affected patients increases. However, studies on ECV progression over time are lacking. We aimed to investigate the progression of ECV and its prognostic impact in CA patients. METHODS AND RESULTS: Serial cardiac magnetic resonance (CMR) examinations, including ECV quantification, were performed in consecutive CA patients. Between 2012 and 2021, 103 CA patients underwent baseline and follow-up CMR, including ECV quantification. Median ECVs at baseline of the total (n = 103), transthyretin [(ATTR) n = 80], and [light chain (AL) n = 23] CA cohorts were 48.0%, 49.0%, and 42.6%, respectively. During a median period of 12 months, ECV increased significantly in all cohorts [change (Δ) +3.5% interquartile range (IQR): -1.9 to +6.9, P < 0.001; Δ +3.5%, IQR: -2.0 to +6.7, P < 0.001; and Δ +3.5%, IQR: -1.6 to +9.1, P = 0.026]. Separate analyses for treatment-naïve (n = 21) and treated (n = 59) ATTR patients revealed that the median change of ECV from baseline to follow-up was significantly higher among untreated patients (+5.7% vs. +2.3%, P = 0.004). Survival analyses demonstrated that median change of ECV was a predictor of outcome [total: hazard ratio (HR): 1.095, 95% confidence interval (CI): 1.047-1.0145, P < 0.001; ATTR: HR: 1.073, 95% CI: 1.015-1.134, P = 0.013; and AL: HR: 1.131, 95% CI: 1.041-1.228, P = 0.003]. CONCLUSION: The present study supports the use of serial ECV quantification in CA patients, as change of ECV was a predictor of outcome and could provide information in the evaluation of amyloid-specific treatments.

Teduglutide in amyloidosis-associated intestinal failure.

Amyloidosis is a heterogeneous disease characterized by tissue deposition of abnormally folded fibrillary proteins that can manifest itself by a wide variety of symptoms depending on the affected organs. GI involvement among amyloidosis patients is common. Its clinical manifestation often presents with nonspecific symptoms such as weight loss, diarrhea, and malabsorption. With no specific treatment existing for GI amyloidosis, therapy focuses on impeding amyloid deposition and managing the patients' symptoms with supportive measures. Here, we present an AL-amyloidosis patient with GI involvement and intestinal failure (IF) who was successfully treated with the glucagon-like peptide-2 (GLP-2) analogue teduglutide. Over the course of treatment with teduglutide, the patient was able to achieve independence from parenteral nutrition and experienced a significant improvement in quality of life (QoL) as stool frequency and consistency improved, urinary output was stabilized and body weight as well as body composition improved over the course of teduglutide therapy. With no longer being exposed to the burden and associated risks of parenteral nutrition, we were able to reduce the potential morbidity and mortality rate as well as to improve the patient's overall QoL. Intestinal tissue biopsy workup revealed a histopathological correlate for the clinical response; Congo-Red-positive intestinal depositions almost completely disappeared within 6 months of teduglutide therapy. Implementing intestinotrophic GLP-2 analogue teduglutide may enrich the spectrum of treatment options for amyloidosis patients with IF who are dependent on parenteral support.

Cardiac amyloidosis: a significant blind spot of the H2FPEF score.

BACKGROUND: Cardiac amyloidosis (CA) often mimics heart failure with preserved ejection fraction (HFpEF). Due to very different treatment strategies, an exact diagnosis and differentiation between pure HFpEF and CA-related heart failure (HF) is important. In the present study, we assessed the recently published H2FPEF score in patients with pure HFpEF, transthyretin (ATTR), as well as light chain (AL) amyloidosis-related HFpEF and tested whether it differentiates between these entities. METHODS: The H2FPEF scores consists of easy-to-assess clinical (Body Mass Index, number of hypertensive drugs, presence of atrial fibrillation, age) and echocardiographic (systolic pulmonary arterial pressure, E/E´) parameters. It can be computed in a categorical way resulting in scores between 0 and 9 points (0-1: HFpEF rule out, 2-5: further testing required, 6-9: HFpEF rule in), or in a continual way providing an exact percentage of a patient's HFpEF probability. Continuous and categorical variables were compared using the Kruskal-Wallis, Mann-Whitney-U, and χ2-tests. Diagnostic accuracy was computed from 2x2 tables. Survival analysis was performed with Kaplan-Meier curves. A P value of <0.05 was set as the level of significance. RESULTS: A total of 100 patients with pure HFpEF, 53 patients with ATTR, and 34 patients with AL CA were included in the present study. Median age (HFpEF: 71.5 years; ATTR CA: 77.0 years; AL CA: 60.0 years; P<0.001), gender distribution (HFpEF [female]: 73.0%, ATTR (female): 18.9%, AL [female]: 38.2%; P<0.001), and N-terminal prohormone of brain natriuretic peptide (HFpEF: 1045pg/mL; ATTR CA: 1927pg/mL; AL CA: 4308pg/mL; P<0.001) differed significantly between study cohorts. Median H2FPEF scores were highest among HFpEF (categorical: 5.0 points; continual: 95.1%), followed by ATTR (categorical: 4.0 points; continual: 89.0%), and AL CA (categorical: 3.0 points; continual: 31.2%). Respective P values were <0.001. Low H2FPEF scores (0-1 points) were found among patients in the AL CA cohort (29.4%), but not among HFpEF or ATTR CA patients (P<0.001). The majority of patients, irrespective of disease entity were in the intermediate score range (2-5 points, HFpEF: 80.0% ATTR CA: 94.3%, AL CA: 67.9%; P=0.006). High scores (6-9 points) were most often found among HFpEF patients (20.0%), followed by ATTR CA (5.7%) and AL CA (2.9%), (P=0.007). CONCLUSIONS: The H2FPEF score should be used with caution, as there is a significant overlap between HFpEF and CA-related HF.

Attrition Rates in Multiple Myeloma Treatment under Real World Conditions-An Analysis from the Austrian Myeloma Registry (AMR).

Multiple myeloma (MM) is characterized by serial relapses, necessitating the application of sequential lines of therapy (LoT). Reports on attrition rates (ARs) vary widely. The present study analysed ARs from the Austrian Myeloma Registry. Attrition was defined as being either deceased, progressive without having received another LoT, or lack of follow-up for ≥5 years. A total of 571 patients diagnosed between January 2009 and August 2021 were included (median age: 72 years; median follow-up: 50.8 months). Some 507 patients received at least one LoT. Of the total, 43.6% underwent autologous stem cell transplantation (SCT, transplant eligible = TE)) with primarily VRd (Bortezomib/Lenalidomide/Dexamethasone) given as induction (26.5%), followed by lenalidomide maintenance in 55.7% of cases. Transplant-ineligible (NTE) patients were predominantly treated with Vd (Bortezomib/Dexamethasone, 21.6%), receiving maintenance in 27.1%. A total of 37.5% received a second LoT. ARs across one to five LoTs were 16.7-27%. Frontline induction/ SCT followed by maintenance reduced ARs associated with age and achievement of deep remission in the frontline. Deep remission prolongs follow-up and time-to-next-treatment (TTNT), while high-risk-cyctogenetics negatively affected these outcomes. Our results demonstrate considerably lower ARs for MM patients within the AMR data versus other healthcare systems. Young age and the achievement of significant remissions after optimal frontline therapy resulted in particularly low ARs. These promising results support a key role for the ease of drug access and reimbursement policies in governing long-term MM patient outcomes.

The management of light chain (AL) amyloidosis in Europe: clinical characteristics, treatment patterns, and efficacy outcomes between 2004 and 2018.

Systemic light-chain (AL) amyloidosis is a rare and debilitating disease. Advances have been made in new treatments in recent years, yet real-world data on the management of the disease are scarce. EMN23 is a retrospective, observational study of patients who initiated first-line treatment in 2004-2018 in Europe, presenting the demographics, clinical characteristics, treatment patterns, and outcomes, from 4480 patients. Regimens based on bortezomib were the most frequently used as first-line therapy; only 6.2% of the patients received autologous stem cell transplant. Hematologic responses improved post-2010 (67.1% vs 55.6% pre-2010). The median overall survival (OS) was 48.8 (45.2-51.7) months; 51.4 (47.3-57.7) months pre-2010 and 46.7 (41.3-52.2) months post-2010. Early mortality was 13.4% and did not improve (11.4% vs 14.4% pre- and post-2010); furthermore, it remained high in patients with advanced cardiac disease (over 39% for stage IIIb). There was a significant improvement for stage IIIa (14.2 vs 30.7 months, p = 0.0170) but no improvement for stage IIIb patients (5.0 vs 4.5 months). This European real-world study of AL-amyloidosis emphasizes the unmet needs of early diagnosis, and the lack of improvement in survival outcomes of the frail stage IIIb population, despite the introduction of new therapies in recent years.

Deep Morphology Learning Enhances Ex Vivo Drug Profiling-Based Precision Medicine.

Drug testing in patient biopsy-derived cells can identify potent treatments for patients suffering from relapsed or refractory hematologic cancers. Here we investigate the use of weakly supervised deep learning on cell morphologies (DML) to complement diagnostic marker-based identification of malignant and nonmalignant cells in drug testing. Across 390 biopsies from 289 patients with diverse blood cancers, DML-based drug responses show improved reproducibility and clustering of drugs with the same mode of action. DML does so by adapting to batch effects and by autonomously recognizing disease-associated cell morphologies. In a post hoc analysis of 66 patients, DML-recommended treatments led to improved progression-free survival compared with marker-based recommendations and physician's choice-based treatments. Treatments recommended by both immunofluorescence and DML doubled the fraction of patients achieving exceptional clinical responses. Thus, DML-enhanced ex vivo drug screening is a promising tool in the identification of effective personalized treatments. SIGNIFICANCE: We have recently demonstrated that image-based drug screening in patient samples identifies effective treatment options for patients with advanced blood cancers. Here we show that using deep learning to identify malignant and nonmalignant cells by morphology improves such screens. The presented workflow is robust, automatable, and compatible with clinical routine. This article is highlighted in the In This Issue feature, p. 476.

Unveiling Cardiac Amyloidosis, its Characteristics, and Outcomes Among Patients With MR Undergoing Transcatheter Edge-to-Edge MV Repair.

BACKGROUND: Mitral regurgitation (MR) and cardiac amyloidosis (CA) both primarily affect older patients. Data on coexistence and prognostic implications of MR and CA are currently lacking. OBJECTIVES: This study sought to identify the prevalence, clinical characteristics, and outcomes of MR CA compared with lone MR. METHODS: Consecutive patients undergoing transcatheter edge-to-edge repair (TEER) for MR at 2 sites were screened for concomitant CA using a multiparametric approach including core laboratory 99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid bone scintigraphy and echocardiography and immunoglobulin light chain assessment. Transthyretin CA (ATTR) was diagnosed by 99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid (Perugini grade 1: early infiltration; grades 2/3: clinical CA) and the absence of monoclonal protein, and light chain (AL) CA via tissue biopsy. All-cause mortality and hospitalization for heart failure (HHF) served as the endpoints. RESULTS: A total of 120 patients (age 76.9 ± 8.1 years, 55.8% male) were recruited. Clinical CA was diagnosed in 14 patients (11.7%; 12 ATTR, 1 AL, and 1 combined ATTR/AL) and early amyloid infiltration in 9 patients (7.5%). Independent predictors of MR CA were increased posterior wall thickness and the presence of a left anterior fascicular block on electrocardiography. Procedural success and periprocedural complications of TEER were similar in MR CA and lone MR (P for all = NS). After a median of 1.7 years, 25.8% had experienced death and/or HHF. MR CA had worse outcomes compared with lone MR (HR: 2.2; 95% CI: 1.0-4.7; P = 0.034), driven by a 2.5-fold higher risk for HHF (HR: 2.5; 95% CI: 1.1-5.9), but comparable mortality (HR: 1.6; 95% CI: 0.4-6.1). CONCLUSIONS: Dual pathology of MR CA is common in elderly patients with MR undergoing TEER and has worse postinterventional outcomes compared with lone MR.

Reverse Remodeling Following Valve Replacement in Coexisting Aortic Stenosis and Transthyretin Cardiac Amyloidosis.

BACKGROUND: Dual pathology of severe aortic stenosis (AS) and transthyretin cardiac amyloidosis (ATTR) is increasingly recognized. Evolution of symptoms, biomarkers, and myocardial mechanics in AS-ATTR following valve replacement is unknown. We aimed to characterize reverse remodeling in AS-ATTR and compared with lone AS. METHODS: Consecutive patients referred for transcatheter aortic valve replacement (TAVR) underwent ATTR screening by blinded 99mTc-DPD bone scintigraphy (Perugini Grade-0 negative, 1-3 increasingly positive) before intervention. ATTR was diagnosed by DPD and absence of monoclonal protein. Reverse remodeling was assessed by comprehensive evaluation before TAVR and at 1 year. RESULTS: One hundred twenty patients (81.8±6.3 years, 51.7% male, 95 lone AS, 25 AS-ATTR) with complete follow-up were studied. At 12 months (interquartile range, 7-17) after TAVR, both groups experienced significant symptomatic improvement by New York Heart Association functional class (both P<0.001). Yet, AS-ATTR remained more symptomatic (New York Heart Association ≥III: 36.0% versus 13.8; P=0.01) with higher residual NT-proBNP (N-terminal pro-brain natriuretic peptide) levels (P<0.001). Remodeling by echocardiography showed left ventricular mass regression only for lone AS (P=0.002) but not AS-ATTR (P=0.5). Global longitudinal strains improved similarly in both groups. Conversely, improvement of regional longitudinal strain showed a base-to-apex gradient in AS-ATTR, whereas all but apical segments improved in lone AS. This led to the development of an apical sparing pattern in AS-ATTR only after TAVR. CONCLUSIONS: Patterns of reverse remodeling differ from lone AS to AS-ATTR, with both groups experiencing symptomatic improvement by TAVR. After AS treatment, AS-ATTR transfers into a lone ATTR cardiomyopathy phenotype.

Corneal Toxicity Associated With Belantamab Mafodotin Is Not Restricted to the Epithelium: Neuropathy Studied With Confocal Microscopy.

PURPOSE: The purpose of this study was to investigate epithelial and neuronal changes in patients with refractory/relapsed multiple myeloma (RRMM) before/during belantamab mafodotin (belamaf) treatment using confocal microscopy. DESIGN: Retrospective case series. METHODS: RRMM patients underwent best-corrected visual acuity (BCVA) testing and slitlamp examination/photography, followed by corneal confocal microscopy (CCM), to evaluate the epithelium and subbasal nerve plexus (SNP) to measure corneal nerve fiber density (CNFD), branch density (CNBD), and fiber length (CNFL) before and during belamaf treatment. RESULTS: In 14 eyes of 7 patients (4 female, 68 ± 10 years of age) with complete follow-up (4 ± 2 months), the median BCVA dropped from 20/25 (20/25-20/20) to 20/40 (20/200-20/32) in the worse eye at the end of follow-up. Microcystic epithelial changes and ocular surface disease were demonstrated biomicroscopically. CCM showed "grape-like" hyperreflective spots in the central basal epithelium that changed to polymorphous-structured cysts in the superficial epithelium, with no pathology detected at the(peri-)limbal structures. The baseline, normal SNP morphology with a mean CNFD, CNBD, and CNFL of 20.25 ± 7.06/mm2, 19.49 ± 12.34/mm2, and 11.8 ± 3.74mm/mm2 respectively, showed severe fiber fragmentation during follow-up, and an observed complete loss of the SNP at the end of follow-up in all eyes. CONCLUSIONS: This study is the first to illustrate neurotoxic effects of belamaf on the human cornea.

Successful treatment of acquired von Willebrand syndrome associated with monoclonal gammopathy : Breaking a dangerous bond.

Acquired von Willebrand syndrome is exceedingly rare and accounts for only 1-3% of von Willebrand disease cases. In this short report, we present our own cases of acquired von Willebrand syndrome associated with monoclonal gammopathy. Both cases went into complete and sustained remission after intensive antimyeloma treatment. The first patient was not deemed fit for autologous stem cell transplantation and was managed with an extensive multidrug combination including daratumumab, carfilzomib, lenalidomide, cyclophosphamide and dexamethasone. After at least VGPR was achieved the coagulation studies rapidly normalized and remained normal after treatment de-escalation to lenalidomide/dexamethasone maintenance. The second patient successfully underwent ASCT after 5 cycles of induction with daratumumab, bortezomib, cyclophosphamide and dexamethasone and has remained in full hematologic and hemostaseologic remission ever since.The two cases highlight the efficacy of aggressive antimyeloma treatment in monoclonal gammopathy-associated acquired von Willebrand syndrome to achieve normalization of coagulation study, providing a possible way to manage these patients.

Convolutional Neural Networks for Fully Automated Diagnosis of Cardiac Amyloidosis by Cardiac Magnetic Resonance Imaging.

AIMS: We tested the hypothesis that artificial intelligence (AI)-powered algorithms applied to cardiac magnetic resonance (CMR) images could be able to detect the potential patterns of cardiac amyloidosis (CA). Readers in CMR centers with a low volume of referrals for the detection of myocardial storage diseases or a low volume of CMRs, in general, may overlook CA. In light of the growing prevalence of the disease and emerging therapeutic options, there is an urgent need to avoid misdiagnoses. METHODS AND RESULTS: Using CMR data from 502 patients (CA: n = 82), we trained convolutional neural networks (CNNs) to automatically diagnose patients with CA. We compared the diagnostic accuracy of different state-of-the-art deep learning techniques on common CMR imaging protocols in detecting imaging patterns associated with CA. As a result of a 10-fold cross-validated evaluation, the best-performing fine-tuned CNN achieved an average ROC AUC score of 0.96, resulting in a diagnostic accuracy of 94% sensitivity and 90% specificity. CONCLUSIONS: Applying AI to CMR to diagnose CA may set a remarkable milestone in an attempt to establish a fully computational diagnostic path for the diagnosis of CA, in order to support the complex diagnostic work-up requiring a profound knowledge of experts from different disciplines.

Stratification for RRMM and Risk-Adapted Therapy: Sequencing of Therapies in RRMM.

The treatment landscape for relapsed multiple myeloma (RRMM) has experienced an unprecedented wave of innovation. Implementation of numerous new substances and drug classes with different modes of action is made possible in routine clinical practice. Next generation proteasome inhibitors, monoclonal antibodies, as well as first in class agents such as selinexor and venetoclax have widened the therapeutic spectrum. This has led to an increase in progression-free and overall survival. Consequently, new challenges for treating physicians in choosing the right treatment at the right stage of the disease have been generated. Several trials support the use of novel agents in the frontline treatment of newly diagnosed multiple myeloma. The use of lenalidomide or bortezomib as a backbone in the first-line setting, requires strategies for treatment once these patients relapse and are refractory to these drugs. Despite the variety of options, selecting the optimal treatment strategy is difficult, since multiple factors have to be considered: patient-specific factors such as age and co-morbidities, as well as myeloma/tumor specific factors such as cytogenetics and relapse kinetics. This review intends to summarize the existing data and guidelines regarding the optimal sequencing of treatments of RRMM using already approved agents as well as agents under investigation.

The Agony of Choice-Where to Place the Wave of BCMA-Targeted Therapies in the Multiple Myeloma Treatment Puzzle in 2022 and Beyond.

Since the introduction of first-generation proteasome inhibitors and immunomodulatory agents, the multiple myeloma (MM) treatment landscape has undergone a remarkable development. Most recently, immunotherapeutic strategies targeting the B cell maturation antigen (BCMA) entered the clinical stage providing access to highly anticipated novel treatment strategies. At present, numerous different approaches investigate BCMA as an effective multi-modal target. Currently, BCMA-directed antibody-drug conjugates, bispecific and trispecific antibodies, autologous and allogeneic CAR-T cell as well as CAR-NK cell constructs are either approved or in different stages of clinical and preclinical development for the treatment of MM. This armamentarium of treatment choices raises several challenges for clinical decision making, particularly in the absence of head-to-head comparisons. In this review, we provide a comprehensive overview of BCMA-targeting therapeutics, deliver latest updates on clinical trial data, and focus on potential patient selection criteria for different BCMA-targeting immunotherapeutic strategies.

Hemophagocytic lymphohistiocytosis in COVID-19: Case reports of a stepwise approach.

RATIONALE: The immunologic syndrome induced by severe acute coronavirus disease 2019 (COVID-19) is yet not fully understood. Typical patterns of clinical and laboratory features match secondary hemophagocytic lymphohistiocytosis (sHLH). However, the optimal approach to COVID-19 patients testing positive for sHLH is still unclear. PATIENT CONCERNS: Three patients with COVID-19 are reviewed. All showed hyperinflammation and cytokine storm, necessitating intensive care treatment including mechanical ventilation. DIAGNOSIS: Secondary hemophagocytic lymphohistiocytosis due to severe COVID-19; diagnosed via HScore. INTERVENTIONS: A treatment regimen of methylprednisolone, pentaglobin, and anakinra was developed and administered. OUTCOMES: One patient survived the ICU stay. Two other patients, in whom sHLH was diagnosed too late, deceased. LESSONS: A routine screening of COVID-19 patients for secondary HLH by using the HScore is feasible; especially those patients deteriorating clinically with no sufficient response to shock management might be at particular high risk. A stepwise therapeutic approach comprising corticosteroids, immunoglobulins and anakinra, accompanied by immunoadsorption, may dampen cytokine storm effects, and potentially reduce mortality.

Prognostic implications of pericardial and pleural effusion in patients with cardiac amyloidosis.

BACKGROUND: Pericardial and pleural effusion are common findings in patients with cardiac amyloidosis (CA). It is not known, whether effusions correlate with right ventricular (RV) function in these patients. Furthermore, data on the prognostic significance of pleural and pericardial effusion in CA is scarce. METHODS: Patients with transthyretin (ATTR) and light chain (AL) CA were included in a clinical registry. All patients underwent transthoracic echocardiography at baseline. The presence of pericardial and pleural effusion was determined in every patient. The clinical endpoint was defined as cardiac death or heart failure hospitalization. RESULTS: In total, 143 patients were analysed. Of these, 85 patients were diagnosed with ATTR and 58 patients with AL. Twenty-four patients presented with isolated pericardial effusion and 35 with isolated pleural effusion. In 19 patients, both pericardial and pleural effusion were found and in 65 patients no effusion was present at baseline. The presence of pleural effusion correlated well with poor RV function, measured by global RV free-wall strain (p = 0.007) in patients with AL, but not in ATTR. No such correlation could be found for pericardial effusion in either amyloidosis subtype. Patients with AL presenting with pleural effusion had worse outcomes compared to patients with pericardial effusion alone or no effusion at baseline. In the ATTR group, there was no difference in outcomes according to presence and type of effusion. CONCLUSION: More than 50% of patients with CA presented with pleural and/or pericardial effusions. While pleural effusion was clearly associated with poor RV function in AL, we were not able to detect this association with pericardial effusion.

CD38 Antibody Daratumumab for the Treatment of Chronic Active Antibody-mediated Kidney Allograft Rejection.

BACKGROUND: Late antibody-mediated rejection (AMR) is a major cause of transplant failure. Potential therapeutic targets are plasma cells and natural killer (NK) cells, both expressing high levels of CD38. METHODS: Here, we report the use of CD38 monoclonal antibody daratumumab (9-mo course) in a kidney allograft recipient diagnosed with smoldering myeloma and anti-HLA class II donor-specific antibody-positive chronic active AMR 13 years after transplantation. Patient monitoring included serial HLA single-antigen testing, peripheral blood immune cell phenotyping, as well as follow-up allograft and bone marrow biopsies at 3 and 9 months, including analyses of rejection-related gene expression patterns. RESULTS: Daratumumab led to persistent CD138+ cell depletion in the bone marrow and blood and substantially decreased NK cells counts in blood and graft tissue. At the same time, donor-specific antibody in serum disappeared, and in vitro alloantibody production by CD138+ cells enriched from bone marrow aspirates was abrogated. A 3-month follow-up biopsy revealed a complete resolution of microcirculation inflammation (g+ptc: 3 to 0) and molecular AMR activity (AMR score: 0.79 to <0.2). The same biopsy showed (subclinical) tubulointerstitial inflammation, which prompted steroid treatment. Over an observation period of 12 months, graft function stabilized. CONCLUSIONS: Targeting CD38 for plasma cell and NK cell depletion may be an effective strategy to counteract AMR. Our results may encourage the design of future trials to clarify the role of this innovative treatment concept in organ transplantation.